Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.

BACKGROUND: EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. METHODS: In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. FINDINGS: Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11.3 months (95% CI 9.6-13.0) compared with 8.8 months (7.7-9.8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1.37, 95% CI 1.07-1.76; p=0.013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥ 3 neutropenia 35 [13%] vs 74 [28%]). INTERPRETATION: Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. FUNDING: Amgen, UK National Institute for Health Research Biomedical Research Centre.

Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials.

BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma. PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect. RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival. CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.

Transformation to "high grade" neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant lung adenocarcinoma.

Several different acquired resistance mechanisms of EGFR mutant lung adenocarcinoma to EGFR-tyrosine kinase inhibitor (TKI) therapy have been described, most recently transformation to small cell lung carcinoma (SCLC). We describe the case of a 46-year-old female with relapsed EGFR exon 19 deletion lung adenocarcinoma treated with erlotinib, and on resistance, cisplatin-pemetrexed. Liver rebiopsy identified an afatinib-resistant combined SCLC and non-small cell carcinoma with neuroendocrine morphology, retaining the EGFR exon 19 deletion. This case highlights acquired EGFR-TKI resistance through transformation to the high-grade neuroendocrine carcinoma spectrum and that that such transformation may not be evident at time of progression on TKI therapy.

ALK translocation is associated with ALK immunoreactivity and extensive signet-ring morphology in primary lung adenocarcinoma.

BACKGROUND: ALK rearrangement is particularly observed in signet-ring sub-type adenocarcinoma. Since fluorescence in situ hybridization (FISH) is not suitable for mass screening, we aimed to characterize the predictive utility of tumour morphology and ALK immunoreactivity to identify ALK rearrangement, in a primary lung adenocarcinoma dataset enriched for signet-ring morphology, compared with that of other morphology. METHODS: 7 adenocarcinomas from diagnostic archives reported with signet-ring morphology were assessed and compared with 11 adenocarcinomas without signet-ring features over the same time period. Growth patterns were reviewed, ALK expression was assessed by standard immunohistochemistry using ALK1 clone and Envision detection (Dako), and ALK rearrangement was assessed by FISH (Abbott Molecular). Associations between groups and predictive utility of tumour morphology and ALK expression using FISH as gold standard were calculated. RESULTS: 2 excision lung biopsy cases with pure (100%) signet-ring morphology and solid patterns demonstrated diffuse moderate cytoplasmic ALK immunoreactivity (2+) and harboured ALK rearrangements (p=0.007), unlike 5 mixed-signet-ring and 11 non-signet-ring adenocarcinomas, which showed negative or 1+ immunoreactivity; and did not harbour ALK rearrangements (p>0.1). ALK expression was not associated with ALK copy number. 6 of 7 cases with signet ring morphology stained for TTF-1. Pure signet-ring morphology and moderate ALK expression were both associated with ALK rearranged tumours. CONCLUSION: ALK rearrangement is strongly associated with ALK immunoreactivity, and was seen only in tumours with pure signet-ring morphology and solid growth pattern. Tumour morphology, growth pattern and ALK immunoreactivity appear to be good indicators of ALK rearrangement, with TTF-1 positivity aiding in proving primary pulmonary origin.

Diagnóstico, estadiamento e tratamento cirúrgico do adenocarcinoma de pâncreas

O adenocarcinoma pancreático é um dos tumores sólidos de pior prognóstico, sendo o tratamento cirúrgico o único potencialmente curativo. Na grande maioria dos pacientes o tumor é diagnosticado em fase avançada, comumente na presença de doença metastática. A introdução de modernos métodos diagnósticos associados ao aperfeiçoamento dos já existentes tem gerado controvérsia quanto à melhor maneira de se estabelecer o diagnóstico e estadiamento do tumor. Da mesma forma, o papel da cirurgia na paliação e aspectos técnicos da ressecção de lesões localizadas estão longe de alcançarem consenso na prática. Método - Revisão da literatura sobre os aspectos controversos relacionados ao tema e um algoritmo para a abordagem dos pacientes com suspeita de tumor de pâncreas são apresentados. Foram utilizados os descritores: “adenocarcinoma” e “pâncreas” para pesquisa no PubMed (www.pubmed.com) e na Bireme (www.bireme.br) e a seguir selecionadas as publicações pertinentes a cada tópico escolhido com atenção especial para metanálises, estudos clínicos controlados, revisões sitemáticas e ainda publicações de grandes centros especializados em doenças pancreáticas. Conclusões - Na suspeita de adenocarcinoma de pâncreas é possível realizar estadiamento muito próximo do real sem a necessidade da exploração cirúrgica sistemática em virtude da disponibilidade na prática de exames modernos e eficientes. Isso permite que paliação menos invasiva seja praticada na maioria dos pacientes com lesões avançadas e incuráveis. Nos em que a cura é possível, a operação deve ser realizada objetivando-se, essencialmente, a remoção da lesão com margens livres e com aceitáveis índices de morbi-mortalidade

Laparoscopic treatment of mucinous adenocarcinoma of jejunum associated with celiac disease. Case report

Mucinous adenocarcinoma of the small bowel is very rare, and only few cases have been described in the literature. Association of this tumor with celiac disease has never been published. The authors report a unique case of jejunal mucinous adenocarcinoma in which a concomitant celiac disease has been histologically recognized. The difficult diagnosis, the role of laparoscopic surgery and the relationship between small bowel tumors and celiac disease are discussed. A 49-year-old man presented with recurrent melena, nausea, vomiting and anemia. A stenosis of the jejunum was documented by means of CT scan and video capsule enteroscopy. A laparoscopy was scheduled. A tumor, found in the first jejunal loop, was removed by laparoscopic surgery. Histopathology revealed a rare mucinous adenocarcinoma associated with epithelial changes secondary to celiac disease. Although small bowel tumors are rare entity, in patients with celiac disease complaining of symptoms related to altered intestinal transit or occult bleeding, an appropriate work-up should be planned for diagnosis. Mucinous type intestinal adenocarcinoma, even if never published before, could be observed. Laparoscopic surgery is often essential for the diagnosis and treatment.

Small bowel adenocarcinoma. Two case reports

Introduction. Small bowel adenocarcinoma is a rare tumor, with a still not well studied tumorigenesis process, and non-specific symptoms that cause a delay in the diagnosis and consequently a worst outcome for the patient. Videocapsule endoscopy (VCE) and double-balloon enteroscopy (DBE) have revolutionized the diagnosis and management of patients with small bowel diseases. Surgery is the treatment of choice when feasible, while the chemotherapeutic approach is still not well standardized. Case reports. Two cases in 2 months (two women 52 and 72-yr-old) of primary bowel adenocarcinoma is reported. The site of the tumor was in jejunum, instead of the most common site in duodenum. The patients underwent DBE with biopsy and ink mark. Laparoscopic-assisted bowel segmental resection was performed. The pathologic diagnosis was primary jejunum adenocarcinoma. No post-operative mortality or significant morbidities were noted. Conclusion. The combination of DBE and laparocopic-assisted bowel surgery represents an ideal diagnostic and therapeutic method.

On the need of standards for reporting on esophageal perforation

Esophageal perforation is associated with significant mortality and morbidity. Its etiology is as heterogenous as modalities currently employed for its treatment. There is no clear evidence which is the treatment of choice for esophageal perforation. This is partly due to the suboptimal quality of available studies and failure to accurately report on the characteristics, treatment and outcome of these patients. Indeed, baseline, operative and outcome data are important for a better evaluation of published data and possibly for including them in meta-analyses of aggregate or individual patient data. We propose a checklist for reporting data on esophageal perforation in order to standardize reporting of data of studies on this severe condition.

Valutazione di effetti citotossici ed emolitici di peptidi ad attività antimicrobica su cellule umane mononucleate del sangue periferico (PBMC) e sulla linea cellulare di adenocarcinoma prostatico PC3

Un film edibile è un sottile strato di materiale commestibile, preformato o formato direttamente sull'alimento, usato come rivestimento o inserito tra i diversi componenti dell'alimento stesso. Per le sue peculiari caratteristiche un film edibile è preparato con materiali commestibili e rappresenta una protezione per l'alimento dall'ambiente esterno. É dunque parte integrante dell'alimento, prolungandone la "shelf-life", ovvero il periodo di utilizzo in commercio del prodotto, dunque il tempo utile tra la data di confezionamento e di scadenza. Una maggiore "shelf-life" comporta molteplici vantaggi per tutti i settori coinvolti nella filiera alimentare: chi produce infatti può offrire ai distributori un prodotto con maggiori garanzie di qualità e conservazione, che distribuisce può allungare il periodo di esposizione negli scaffali e di stoccaggio nei magazzini, chi consuma ottiene un prodotto più sicuro e che può essere conservato più a lungo. I film edibili inoltre sono dotati di proprietà peculiari, infatti conferiscono protezione agli alimenti, costituendo un'interfaccia tra prodotto e ambiente e rallentando il decadimento qualitativo; hanno una natura ecologica perchè non incidono sull'inquinamento ambientale essendo commestibili; sono funzionali, poichè oltre al ruolo di imballaggio, possono assumere funzione antimicrobica e funzionale.

Diagnóstico, estadiamento e tratamento cirúrgico do adenocarcinoma de pâncreas

O adenocarcinoma pancreático é um dos tumores sólidos de pior prognóstico, sendo o tratamento cirúrgico o único potencialmente curativo. Na grande maioria dos pacientes o tumor é diagnosticado em fase avançada, comumente na presença de doença metastática. A introdução de modernos métodos diagnósticos associados ao aperfeiçoamento dos já existentes tem gerado controvérsia quanto à melhor maneira de se estabelecer o diagnóstico e estadiamento do tumor. Da mesma forma, o papel da cirurgia na paliação e aspectos técnicos da ressecção de lesões localizadas estão longe de alcançarem consenso na prática. Método - Revisão da literatura sobre os aspectos controversos relacionados ao tema e um algoritmo para a abordagem dos pacientes com suspeita de tumor de pâncreas são apresentados. Foram utilizados os descritores: “adenocarcinoma” e “pâncreas” para pesquisa no PubMed (www.pubmed.com) e na Bireme (www.bireme.br) e a seguir selecionadas as publicações pertinentes a cada tópico escolhido com atenção especial para metanálises, estudos clínicos controlados, revisões sitemáticas e ainda publicações de grandes centros especializados em doenças pancreáticas. Conclusões - Na suspeita de adenocarcinoma de pâncreas é possível realizar estadiamento muito próximo do real sem a necessidade da exploração cirúrgica sistemática em virtude da disponibilidade na prática de exames modernos e eficientes. Isso permite que paliação menos invasiva seja praticada na maioria dos pacientes com lesões avançadas e incuráveis. Nos em que a cura é possível, a operação deve ser realizada objetivando-se, essencialmente, a remoção da lesão com margens livres e com aceitáveis índices de morbi-mortalidade

Association between common lipid metabolism genes polymorphisms and sporadic colorectal adenocarcinoma risk

Lipids can modulate the risk of developing sporadic colorectal adenocarcinoma (SCA), since alterations into lipid metabolism and transport pathways influence directly cholesterol and lipids absorption by colonic cells and indirectly reactive oxygen species (ROS) synthesis in rectum cells due to lipid accumulation. Lipid metabolism is regulated by several proteins APOA1, APOB, APOC3, APOE, CETP, NPY, PON1 and PPARG that could influence both metabolism and transport processes. Is been reported that several common single-nucleotide polymorphisms (SNPs) in these genes could influence their function and/or expression, changing lipid metabolism balance. Thus, genetic changes in those genes can influence SCA development, once the majority of them were never studied in this disease. Furthermore, there are contradictory results between some studied polymorphisms and SCA risk. Thus, the aim of this study was to explore and describe lipid metabolism-associated genes common polymorphisms (APOA1 -75 G>A; APOB R3500Q; APOC3 C3175G, APOC3 T3206G; APOE Cys112/158Arg; CETP G279A, CETP R451Q; NPY Leu7Pro; PON1 Q192R; PPARG Pro12Ala) status among SCA, and their relationship with SCA risk. Genotyping of common lipid metabolism genes polymorphisms (APOA1 75 G>A; APOB R3500Q; APOC3 C3175G, APOC3 T3206G; APOE Cys112/158Arg; CETP G279A, CETP R451Q; NPY Leu7Pro; PON1 Q192R; PPARG Pro12Ala) were done by PCR-SSP techniques, from formalin-fixed and paraffin-embedded biopsies of 100 healthy individuals and 68 SCA subjects. Mutant genotypes of APOA1 -75AA (32% vs 12%; p=0.001; OR=3.51; 95% CI 1.59-7.72); APOB 3500AA (7% vs 0%; p=0.01); APOC3 3175GG (19% vs 2%; p=0.0002; OR=11.58; 95% CI 2.52-53.22), APOC3 3206GG (19% vs 0%; p<0.0001); CETP 279AA (12% vs 1%; p=0.003; OR=13.20; 95% CI 1.61-108.17), CETP 451AA (16% vs 0%; p<0.0001); NPY 7CC (15% vs 0%; p<0.0001); PPARG 12GG (10% vs 0%; p=0.001); and heterozygote genotype PON1 192AG (56% vs 22%; p<0.0001; OR=4.49; 95% CI 2.298.80) were found associated with SCA prevalence. While, APOE E4/E4 (0% vs 8%; p=0.02) mutant haplotype seemed to have a protective effect on SCA. Moreover, it also been founded differences between APOB 3500GA, APOC3 3206TG, CETP 279AA genotypes and PPARG 12Ala allele prevalence and tissue localization (colon vs rectum). These findings suggest a positive association between most of common lipid metabolism genes polymorphisms studied and SCA prevalence. Dysregulation of APOA1, APOB, APOC3, CETP, NPY, PON1 and PPARG genes could be associated with lower cholesterol plasma levels and increase ROS among colon and rectum mucosa. Furthermore, these results also support the hypothesis that CRC is related with intestinal lipid absorption decrease and secondary bile acids production increase. Moreover, the polymorphisms studied may play an important role as biomarkers to SCA susceptibility.

Association between common lipid metabolism genes polymorphisms and sporadic colorectal adenocarcinoma risk

Lipids can modulate the risk of developing sporadic colorectal adenocarcinoma (SCA), since alterations into lipid metabolism and transport pathways influence directly cholesterol and lipids absorption by colonic cells and indirectly reactive oxygen species (ROS) synthesis in rectum cells due to lipid accumulation. Lipid metabolism is regulated by several proteins APOA1, APOB, APOC3, APOE, CETP, NPY, PON1 and PPARG that could influence both metabolism and transport processes. Is been reported that several common single-nucleotide polymorphisms (SNPs) in these genes could influence their function and/or expression, changing lipid metabolism balance. Thus, genetic changes in those genes can influence SCA development, once the majority of them were never studied in this disease. Furthermore, there are contradictory results between some studied polymorphisms and SCA risk. Thus, the aim of this study was to explore and describe lipid metabolism-associated genes common polymorphisms (APOA1 -75 G>A; APOB R3500Q; APOC3 C3175G, APOC3 T3206G; APOE Cys112/158Arg; CETP G279A, CETP R451Q; NPY Leu7Pro; PON1 Q192R; PPARG Pro12Ala) status among SCA, and their relationship with SCA risk. Genotyping of common lipid metabolism genes polymorphisms (APOA1 75 G>A; APOB R3500Q; APOC3 C3175G, APOC3 T3206G; APOE Cys112/158Arg; CETP G279A, CETP R451Q; NPY Leu7Pro; PON1 Q192R; PPARG Pro12Ala) were done by PCR-SSP techniques, from formalin-fixed and paraffin-embedded biopsies of 100 healthy individuals and 68 SCA subjects. Mutant genotypes of APOA1 -75AA (32% vs 12%; p=0.001; OR=3.51; 95% CI 1.59-7.72); APOB 3500AA (7% vs 0%; p=0.01); APOC3 3175GG (19% vs 2%; p=0.0002; OR=11.58; 95% CI 2.52-53.22), APOC3 3206GG (19% vs 0%; p<0.0001); CETP 279AA (12% vs 1%; p=0.003; OR=13.20; 95% CI 1.61-108.17), CETP 451AA (16% vs 0%; p<0.0001); NPY 7CC (15% vs 0%; p<0.0001); PPARG 12GG (10% vs 0%; p=0.001); and heterozygote genotype PON1 192AG (56% vs 22%; p<0.0001; OR=4.49; 95% CI 2.298.80) were found associated with SCA prevalence. While, APOE E4/E4 (0% vs 8%; p=0.02) mutant haplotype seemed to have a protective effect on SCA. Moreover, it also been founded differences between APOB 3500GA, APOC3 3206TG, CETP 279AA genotypes and PPARG 12Ala allele prevalence and tissue localization (colon vs rectum). These findings suggest a positive association between most of common lipid metabolism genes polymorphisms studied and SCA prevalence. Dysregulation of APOA1, APOB, APOC3, CETP, NPY, PON1 and PPARG genes could be associated with lower cholesterol plasma levels and increase ROS among colon and rectum mucosa. Furthermore, these results also support the hypothesis that CRC is related with intestinal lipid absorption decrease and secondary bile acids production increase. Moreover, the polymorphisms studied may play an important role as biomarkers to SCA susceptibility.